Therapeutic compounds

ABSTRACT

Disclosed herein are compounds of the formula 
     
       
         
         
             
             
         
       
     
     or salts or bioisosteres thereof. Therapeutic methods, medicaments, and compositions related thereto are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/187,018, filed on Aug. 6, 2008, which is a continuation of U.S. Pat.No. 7,429,669, issued on Sep. 30, 2008, incorporated by referenceherein, which claims the benefit of U.S. Provisional Application Ser.No. 60/805,285, filed Jun. 20, 2006, which is hereby incorporated byreference in its entirety.

DESCRIPTION OF THE INVENTION

Disclosed herein are compounds of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 14 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 14 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2,    3, 4, 5 or 6 carbon atoms;-   J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN;    O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2,    3, 4, 5, or 6 carbon atoms; or CF₃; and-   B is aryl or heteroaryl.

Also disclosed herein is a carboxylic acid or a bioisostere thereof,said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2,    3, 4, 5 or 6 carbon atoms ;-   J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN;    O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2,    3, 4, 5, or 6 carbon atoms; or CF₃; and-   B is aryl or heteroaryl.

Any structure depicted herein, whether alone or presented with otherstructures, is contemplated as an individual embodiment.

Furthermore, for each individual structure presented herein, anembodiment is contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure,and/or one or more pharmaceutically acceptable salts of the compounds ofthe structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more pharmaceutically acceptable salts of thecompounds of the structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure.

Since a dashed line represents the presence or absence of a bond,compounds such as those according to the structures below are possible.

“Bioisosteres are substituents or groups that have chemical or physicalsimilarities, and which produce broadly similar biological properties.”Silverman, Richard B., The Organic Chemistry of Drug Design and DrugAction, 2^(nd) Edition, Amsterdam: Elsevier Academic Press, 2004, p. 29.

While not intending to be limiting, organic acid functional groups arebioisoteres of carboxylic acids. An organic acid functional group is anacidic functional group on an organic molecule. While not intending tobe limiting, organic acid functional groups may comprise an oxide ofcarbon, sulfur, or phosphorous. Thus, while not intending to limit thescope of the invention in any way, in certain compounds Y is acarboxylic acid, sulfonic acid, or phosphonic acid functional group.

Additionally, an amide or ester of one of the organic acids mentionedabove comprising up to 14 carbon atoms is also contemplated. In anester, a hydrocarbyl moiety replaces a hydrogen atom of an acid such asin a carboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H. The following amides are also specifically contemplated,CONSO₂-biphenyl, CONSO₂-phenyl, CONSO₂-heteroaryl, and CONSO₂-naphthyl.The biphenyl, phenyl, heteroaryl, or naphthyl may be substituted orunsubstituted.

Han et. al. (Biorganic & Medicinal Chemistry Letters 15 (2005)3487-3490) has recently shown that the groups shown below are suitablebioisosteres for a carboxylic acid. The activity of compounds with thesegroups in inhibiting HCV NS3 protease was comparable to or superior tosimilar compounds where the group is replaced by CO₂H. Thus, Y could beany group depicted below.

Carboxylic Acid Bioisosteres According to Han et. al.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 14 carbonatoms. An ether is a functional group wherein a hydrogen of an hydroxylis replaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc. These groupsare also bioisosteres of a carboxylic acid.

“Up to 14 carbon atoms” means that the entire Y moiety, including thecarbonyl carbon of a carboxylic acid ester or amide, and both carbonatoms in the —CH₂O—C of an ether has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group.

While not intending to be limiting, examples of compounds having theidentified Y are depicted below. In these examples R is H orhydrocarbyl, subject to the constraints defined herein. Each structurebelow represents a specific embodiment which is individuallycontemplated, as well as pharmaceutically acceptable salts and prodrugsof compounds which are represented by the structures. However, otherexamples are possible which may not fall within the scope of thestructures shown below.

Organic Acids Esters Amides M¹—CO₂H M¹—CO₂R M¹—CO₂NR₂ Carboxylic AcidCarboxylic Acid Ester Carboxylic Acid Amide M¹—P(O)(OH)₂ M¹—P(O)(OH)RM¹—P(O)(OH)NR₂ Phosponic Acid Phosphonic Acid Ester Phosphonic AcidAmide M¹—SO₃H M¹—SO₃R M¹—SO₃NR₂ Sulfonic Acid Sulfonic Acid EsterSulfonic Acid Amide M¹—CH₂OH M¹—CH₂OR Y is hydroxymethyl Ether

A tetrazolyl functional group is another bioisostere of a carboxylicacid. An unsubstituted tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

In one embodiment, Y is an organic acid functional group, or an amide orester thereof comprising up to 14 carbon atoms; or Y is hydroxymethyl oran ether thereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group.

In another embodiment, Y is CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

According to Silverman (p. 30), the moieties shown below are alsobioisosteres of a carboxylic acid.

Carboxylic Acid Bioisosteres According to Silverman

Orlek et al. (J. Med. Chem. 1991, 34, 2726-2735) described oxadiazolesas suitable bioisosteres for a carboxylic acid. These ester replacementswere shown to be potent muscarinic agonists having improved metabolicstability. Oxadiazoles were also described by Anderson et al. (Eur. J.Med. Chem. 1996, 31, 417-425) as carboxamide replacements havingimproved in vivo efficacy at the benzodiazepine receptor.

Carboxylic Acid Bioisosteres According to Orlek et. al.

Kohara et al. (J. Med. Chem. 1996, 39, 5228-5235) described acidicheterocycles as suitable bioisosteres for a tetrazole. These carboxylicacid replacements were shown to be potent angiotensin II receptorantagonists having improved metabolic stability.

Tetrazole Bioisosteres According to Kohara et. al.

Drysdale et al. (J. Med. Chem. 1992, 35, 2573-2581) have describedcarboxylic acid mimics of non-peptide CCK-B receptor antagonists. Thebinding affinities of many of the bioisosteres are similar to the parentcarboxylic acid.

Carboxylic Acid Bioisosteres According to Drysdale et. al.

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S or O. For example, whilenot intending to limit the scope of the invention in any way, A may be amoiety where S replaces one or two carbon atoms such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way,

-   in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar,    e.g. —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—,    —(CH₂)₂—Ar—(CH₂)₂—, and the like;-   in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties;    and Ar, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,    —O—CH₂—Ar—(CH₂)₂, and the like; or-   in another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties;    and Ar, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —13 CH₂—Ar—,    —S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ^(−K) ⁺ salt. Any cation ofthe salt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

-   hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,    alkenyl, alkynyl, and the like;-   hydrocarbyloxy up to C₃;-   organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and salts    thereof;-   CF₃;

halo, such as F, Cl, or Br;

-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents such as CN, NO₂, and the like;-   and the like.

In one embodiment A is —(CH₂)_(m)-Ph-(CH₂)_(o)— wherein the sum of m ando is 1, 2, or 3, and wherein one CH₂ may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph is attached at the 1 and 3positions, otherwise known as m-interphenylene, such as when A has thestructure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)3S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)3-.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl. In another embodiment A is—(CH₂)₃Ar—, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—, —(CH₂)₂OAr, —O(CH₂)₂Ar—,—CH₂OCH₂Ar—, or —(CH₂)₂OAr, wherein Ar is monocyclic interheteroarylene.

In another embodiment Ar is interthienylene.

In another embodiment Ar is interthiazolylene.

In another embodiment Ar is interoxazolylene.

Compounds according to the each of the structures depicted below arepossible.

U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

In one embodiment, U¹ is O.

In one embodiment, U¹ is S.

In one embodiment, U¹ is F.

In one embodiment, U¹ is Cl.

In one embodiment, U¹ is Br.

In one embodiment, U¹ is I.

In one embodiment, U¹ is CN.

In one embodiment, U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃.

In one embodiment, J¹ is hydrogen.

In one embodiment, J¹ is F.

In one embodiment, J¹ is Cl.

In one embodiment, J¹ is Br.

In one embodiment, J¹ is I.

In one embodiment, J¹ is O.

In one embodiment, J¹ is OH.

In one embodiment, J¹ is CN.

In one embodiment, J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J¹ is CF₃.

In one embodiment, J² is hydrogen.

In one embodiment, J² is F.

In one embodiment, J² is Cl.

In one embodiment, J² is Br.

In one embodiment, J² is I.

In one embodiment, J² is O.

In one embodiment, J² is OH.

In one embodiment, J² is CN.

In one embodiment, J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J² is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J² is CF₃.

Thus, compounds according to the structures shown below are possible.

B is aryl or heteroaryl.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt. Any cation of the salt is not counted in the 20 non-hydrogenatoms. Thus, while not intending to limit the scope of the invention inany way, a substituent may be:

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, alkenyl, alkynyl, and the like, including linear,    branched or cyclic hydrocarbyl, and combinations thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 19 carbon atoms;-   other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the    like;-   thioether substituents including S-hydrocarbyl and other thioether    substituents;-   hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,    etc, up to 19 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like-   fluorocarbyl, such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl and are also substitutedphenyl. For this type of polycyclic ring system, an aromatic orheteroaromatic ring, not a non-aromatic ring, must be attached to theremainder of the molecule, i.e. the part of the molecule that is not B.In other words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

-   Alkyl is hydrocarbyl having no double or triple bonds including:-   linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl,    n-hexyl, and the like;-   branched alkyl such as isopropyl, branched butyl isomers (i.e.    sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e.    isopentyl, etc), branched hexyl isomers, and higher branched alkyl    fragments;-   cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.; and-   alkyl fragments consisting of both cyclic and noncyclic components,    whether linear or branched, which may be attached to the remainder    of the molecule at any available position including terminal,    internal, or ring carbon atoms.-   Alkenyl is hydrocarbyl having one or more double bonds including-   linear alkenyl, branched alkenyl, cyclic alkenyl, and combinations    thereof in analogy to alkyl.-   Alkynyl is hydrocarbyl having one or more triple bonds including    linear alkynyl, branched alkynyl, cyclic alkynyl and combinations    thereof in analogy to alkyl.-   Aryl is an unsubstituted or substituted aromatic ring or ring system    such as phenyl, naphthyl, biphenyl, and the like. Aryl may or may    not be hydrocarbyl, depending upon whether it has substituents with    heteroatoms.-   Arylalkyl is alkyl which is substituted with aryl. In other words    alkyl connects aryl to the remaining part of the molecule. Examples    are —CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may    not be hydrocarbyl, depending upon whether the aryl portion has    substituents with heteroatoms.-   Unconjugated dienes or polyenes have one or more double bonds which    are not conjugated. They may be linear, branched, or cyclic, or a    combination thereof.-   Combinations of the above are also possible.

In another embodiment, B is substituted or unsubstituted phenyl.

In another embodiment, B is substituted or unsubstituted thienyl.

In another embodiment, B is substituted or unsubstituted naphthyl.

In another embodiment, B is substituted or unsubstituted furyl.

In another embodiment, B is substituted or unsubstituted pyridinyl.

In another embodiment, B is substituted or unsubstituted benzothienyl.

In another embodiment, B is substituted or unsubstituted indanyl.

In another embodiment, B is substituted or unsubstituted tetralonyl.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oxygen,sulfur, or atoms; and wherein all substituents taken together consist of0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7,8 or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, 0, 1, 2 or 3 oxygen atoms; 0, 1, 2, or 3 sulfur atoms; 0, 1, 2,or 3 nitrogen atoms.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oroxygen atoms; and wherein all substituents taken together consist of 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, and 0, 1, 2 or 3 oxygen atoms.

In another embodiment, B has a substituent of the formulaC_(a)H_(b)O_(c); wherein a is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, b is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; and cis 0, 1, 2, or 3.

In another embodiment, B has 1, 2, 3, or 4 alkyl substituents having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has a hydroxyalkyl substituent having 0, 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or 2 hydroxy moieties.

In another embodiment, B has an alkyl substituent having 0, 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has 1, 2, 3, or 4 halogen substituents.

In another embodiment, B has 1, 2, 3, or 4 chloro substituents.

In another embodiment, B has 1 chloro substituent.

In another embodiment, B has 2 chloro substituents.

In another embodiment, B has 1, 2, 3, or 4 trifluoromethyl substituents.

In another embodiment, B has 1, 2, or 3 trifluoromethyl substituents.

In another embodiment, B has 1 trifluoromethyl substituent.

In another embodiment, B has 2 trifluoromethyl substituents.

In another embodiment, B has a hydroxyl substituent.

Examples of useful moieties for B are depicted below. Each isindividually contemplated as an embodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 14 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 14 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2,    3, 4, 5 or 6 carbon atoms;-   J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN;    O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2,    3, 4, 5, or 6 carbon atoms; or CF₃; and-   B is aryl or heteroaryl.

Compound Example 2

A compound which is a carboxylic acid or a bioisostere thereof, saidcarboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2,    3, 4, 5 or 6 carbon atoms;-   J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN;    O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2,    3, 4, 5, or 6 carbon atoms; or CF3; and-   B is aryl or heteroaryl.

Compound Example 3

A compound according to claim 1 wherein Y is selected from CO₂R²,CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

Compound Example 4

A compound according to claim 1 or 3 of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof

Compound Example 5

A compound according to claim 1 or 3 of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof

Compound Example 6

A compound according to claim 1 or 3 of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof

Compound Example 7

A compound according to any one of claims 1 to 6 wherein A is(3-methylphenoxy)methyl.

Compound Example 8

A compound according to any one of claims 1 to 6 wherein A is(4-but-2-ynyloxy)methyl.

Compound Example 9

A compound according to any one of claims 1 to 6 wherein A is2-(2-ethylthio)thiazol-4-yl.

Compound Example 10

A compound according to any one of claims 1 to 6 wherein A is2-(3-propyl)thiazol-5-yl.

Compound Example 11

A compound according to any one of claims 1 to 6 wherein A is3-(methoxymethyl)phenyl.

Compound Example 12

A compound according to any one of claims 1 to 6 wherein A is3-(3-propyl)phenyl.

Compound Example 13

A compound according to any one of claims 1 to 6 wherein A is3-methylphenethyl.

Compound Example 14

A compound according to any one of claims 1 to 6 wherein A is4-(2-ethyl)phenyl.

Compound Example 15

A compound according to any one of claims 1 to 6 wherein A is4-phenethyl.

Compound Example 16

A compound according to any one of claims 1 to 6 wherein A is4-methoxybutyl.

Compound Example 17

A compound according to any one of claims 1 to 6 wherein A is5-(methoxymethyl)furan-2-yl.

Compound Example 18

A compound according to any one of claims 1 to 6 wherein A is5-(methoxymethyl)thiophen-2-yl.

Compound Example 19

A compound according to any one of claims 1 to 6 wherein A is5-(3-propyl)furan-2-yl.

Compound Example 20

A compound according to any one of claims 1 to 6 wherein A is5-(3-propyl)thiophen-2-yl.

Compound Example 21

A compound according to any one of claims 1 to 6 wherein A is 6-hexyl.

Compound Example 22

A compound according to any one of claims 1 to 6 wherein A is(Z)-6-hex-4-enyl.

Compound Example 23

A compound according to any one of claims 1, 3, 4 and 7 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 24

A compound according to any one of claims 1, 3, and 7 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 25

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 26

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 27

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 28

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 29

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 30

A compound according to any one of claims 1, 3, and 6 to 22 having theformula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 31

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is O.

Compound Example 32

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is S.

Compound Example 33

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is F.

Compound Example 34

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is Cl.

Compound Example 35

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is Br.

Compound Example 36

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is I.

Compound Example 37

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is CN.

Compound Example 38

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 39

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is hydrogen.

Compound Example 40

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is F.

Compound Example 41

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is Cl.

Compound Example 42

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J′ is Br.

Compound Example 43

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is I.

Compound Example 44

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is O.

Compound Example 45

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is OH.

Compound Example 46

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is CN.

Compound Example 47

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 48

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

Compound Example 49

A compound according to any one of claims 1 to 3, and 7 to 22, and 31 to38 wherein J¹ is CF₃.

Compound Example 50

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is hydrogen.

Compound Example 51

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is F.

Compound Example 52

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is Cl.

Compound Example 53

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is Br.

Compound Example 54

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is I.

Compound Example 55

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is O.

Compound Example 56

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is OH.

Compound Example 57

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is CN.

Compound Example 58

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 59

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

Compound Example 60

A compound according to any one of claims 1 to 3, 7 to 22, and 31 to 49wherein J² is CF₃.

Compound Example 61

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted phenyl.

Compound Example 62

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted thienyl.

Compound Example 63

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted naphthyl.

Compound Example 64

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted furyl.

Compound Example 65

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted pyridinyl.

Compound Example 66

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted benzothienyl.

Compound Example 67

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted indanyl.

Compound Example 68

A compound according to any one of claims 1 to 60 wherein B issubstituted or unsubstituted tetralonyl.

Compound Example 69

A compound according to any one of claims 1 to 60 wherein B has 1, 2, 3,4, or 5 substituents, wherein each substituent has one or more carbon,fluorine, chlorine, bromine, or oxygen atoms; and wherein allsubstituents taken together consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 0, 1, 2or 3 chlorine atoms, 0, 1, 2 or 3 bromine atoms, and 0, 1, 2 or 3 oxygenatoms.

Compound Example 70

A compound according to any one of claims 1 to 60 wherein B has asubstituent of the formula C_(a)H_(b)O_(c); wherein a is 0, 1, 2, 3, 4,5, 6, 7, 8 or 9, b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18 or 19; and c is 0, 1, 2, or 3.

Compound Example 71

A compound according to any one of claims 1 to 60 wherein B has 1, 2, 3,or 4 alkyl substituents having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbonatoms.

Compound Example 72

A compound according to any one of claims 1 to 60 wherein B has ahydroxyalkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms and 1 or 2 hydroxy moieties.

Compound Example 73

A compound according to any one of claims 1 to 60 wherein B has an alkylsubstituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

Compound Example 74

A compound according to any one of claims 1 to 60 wherein B has 1, 2, 3,or 4 halogen substituents.

Compound Example 75

A compound according to any one of claims 1 to 60 wherein B has 1, 2, 3,or 4 chloro substituents.

Compound Example 76

A compound according to any one of claims 1 to 60 wherein B has 1 chlorosubstituent.

Compound Example 77

A compound according to any one of claims 1 to 60 wherein B has 2 chlorosubstituents.

Compound Example 78

A compound according to any one of claims 1 to 60 wherein B has 1, 2, 3,or 4 trifluoromethyl substituents.

Compound Example 79

A compound according to any one of claims 1 to 60 wherein B has 1, 2, or3 trifluoromethyl substituents.

Compound Example 80

A compound according to any one of claims 1 to 60 wherein B has 1trifluoromethyl substituent.

Compound Example 81

A compound according to any one of claims 1 to 60 wherein B has 2trifluoromethyl substituents.

Compound Example 82

A compound according to any one of claims 1 to 60 wherein B has ahydroxyl substituent.

Compound Example 83

A compound according to any one of claims 1 to 61 wherein B isunsubstituted phenyl.

Compound Example 84

A compound according to any one of claims 1 to 61 wherein B is3,5-dichlorophenyl.

Compound Example 85

A compound according to any one of claims 1 to 61 wherein B is3,5-di(trifluoromethyl)phenyl.

Compound Example 86

A compound according to any one of claims 1 to 61 wherein B is2-chlorophenyl.

Compound Example 87

A compound according to any one of claims 1 to 61 wherein B is3-chlorophenyl.

Compound Example 88

A compound according to any one of claims 1 to 61 wherein B is4-chlorophenyl.

Compound Example 89

A compound according to any one of claims 1 to 61 wherein B is3-(trifluoromethyl)phenyl.

Compound Example 90

A compound according to any one of claims 1 to 61 wherein B is3-isopropylphenyl.

Compound Example 91

A compound according to any one of claims 1 to 61 wherein B is3-tert-butylphenyl.

Compound Example 92

A compound according to any one of claims 1 to 61 wherein B is3-hydroxyphenyl.

Compound Example 93

A compound according to any one of claims 1 to 61 wherein B is3-methoxyphenyl.

Compound Example 94

A compound according to any one of claims 1 to 61 wherein B is3-(benzoyloxy)phenyl.

Compound Example 95

A compound according to any one of claims 1 to 61 wherein B is2,3-dimethylphenyl.

Compound Example 96

A compound according to any one of claims 1 to 61 wherein B is3,4-dimethylphenyl.

Compound Example 97

A compound according to any one of claims 1 to 61 wherein B is2,4-dimethylphenyl.

Compound Example 98

A compound according to any one of claims 1 to 61 wherein B is2,5-dimethylphenyl.

Compound Example 99

A compound according to any one of claims 1 to 61 wherein B is3,5-dimethylphenyl.

Compound Example 100

A compound according to any one of claims 1 to 61 wherein B is2,6-dimethylphenyl.

Compound Example 101

A compound according to any one of claims 1 to 61 wherein B is3-(hydroxymethyl)phenyl.

Compound Example 102

A compound according to any one of claims 1 to 61 wherein B is3-(1-hydroxyethyl)phenyl.

Compound Example 103

A compound according to any one of claims 1 to 61 wherein B is3-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 104

A compound according to any one of claims 1 to 61 wherein B is2-(hydroxymethyl)phenyl.

Compound Example 105

A compound according to any one of claims 1 to 61 wherein B is4-(hydroxymethyl)-3,5-dimethylphenyl.

Compound Example 106

A compound according to any one of claims 1 to 61 wherein B is4-(methoxymethyl)-3,5-dimethylphenyl.

Compound Example 107

A compound according to any one of claims 1 to 61 wherein B is3-(1-hydroxybutyl)phenyl.

Compound Example 108

A compound according to any one of claims 1 to 61 wherein B is4-(1-methoxybutyl)phenyl.

Compound Example 109

A compound according to any one of claims 1 to 61 wherein B is4-(1-hydroxybutyl)phenyl.

Compound Example 110

A compound according to any one of claims 1 to 61 wherein B is4-(2-hydroxyethyl)phenyl.

Compound Example 111

A compound according to any one of claims 1 to 61 wherein B is3-(2-hydroxyethyl)phenyl.

Compound Example 112

A compound according to any one of claims 1 to 61 wherein B is2-(2-hydroxyethyl)phenyl.

Compound Example 113

A compound according to any one of claims 1 to 61 wherein B is4-(2-hydroxyethyl)-3,5-dimethylphenyl.

Compound Example 114

A compound according to any one of claims 1 to 61 wherein B is3-(1-hydroxyhexyl)phenyl.

Compound Example 115

A compound according to any one of claims 1 to 61 wherein B is3-(acetoxymethyl)-5-chlorophenyl.

Compound Example 116

A compound according to any one of claims 1 to 61 wherein B is1-oxo-2,3-dihydro-1H-inden-4-yl.

Compound Example 117

A compound according to any one of claims 1 to 61 wherein B is1-hydroxy-2,3-dihydro-1H-inden-4-yl.

Compound Example 118

A compound according to any one of claims 1 to 61 wherein B is5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl.

Compound Example 119

A compound according to any one of claims 1 to 61 wherein B is3-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 120

A compound according to any one of claims 1 to 61 wherein B is4-(2-phenylpropan-2-yl)phenyl.

Compound Example 121

A compound according to any one of claims 1 to 60 wherein B isnaphthalen-2-yl.

Compound Example 122

A compound according to any one of claims 1 to 60 wherein B isnaphthalen-1-yl.

Compound Example 123

A compound according to any one of claims 1 to 60 wherein B is4-chloronaphthalen-1-yl.

The following are hypothetical examples of compositions, kits, methods,uses, and medicaments employing the hypothetical compound examples.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 123, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 123 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Use of a compound according to any one of compound examples 1 to 123 inthe manufacture of a medicament for the treatment of baldness in aperson.

A medicament comprising a compound according to any one of compoundexamples 1 to 123, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 123 to a mammal for the treatment of glaucoma orocular hypertension.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 123, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

Synthetic Methods

Synthetic Example 15-{3-[(1S,5S)-5-(3-Chloro-5-hydroxymethyl-phenoxymethyl)-4-oxo-cyclopent-2-enyl]-propyl}-thiophene-2-carboxylicacid (13)

Step 1. Wittig reaction of lactol 1 and phosphonate 2 to afford alkene 3

Potassium carbonate (99.99%, 2.25 g, 16.3 mmol) was added to phosphonate2 (see Collect. Czech. Chem. Commun. 1994, 58, 138-148, 2.90 g, 6.40mmol) in DMF (11 mL) at 0° C. After 30 min at 0° C., a solution of knownlactol 1 (1.20 g, 3.22 mmol) in DMF (11 mL+10 mL) was added. Thereaction mixture was allowed to rt and stirred overnight. The reactionmixture was then poured into water and extracted with EtOAc (3×). Thecombined extracts were washed with brine then dried (MgSO₄), filteredand concentrated in vacuo. Purification of the crude residue by flashcolumn chromatography on silica gel (hexane→30% EtOAc/hexane, gradient)afforded 1.50 g (91%) of alkene 3.

Step 2. Hydrogenation of alkene 3 to give 4

Palladium on carbon (10 wt. %, 321 mg) was added to a solution of alkene3 (1.50 g, 2.94 mmol) in EtOAc (59 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (5×) and thereaction mixture was stirred under a balloon of hydrogen for 6 h. Thereaction mixture was filtered through celite, washing with EtOAc, andthe filtrate was concentrated in vacuo to afford 1.51 g (quant.) ofsaturated compound 4.

Step 3. Mesylation of 4 to give 5

Triethylamine (316 μL, 2.27 mmol) and methanesulfonyl chloride (142 μL,1.80 mmol) were added sequentially to a solution of 4 (769 mg, 1.50mmol) in CH₂Cl₂ (11.3 mL) at 0° C. The reaction mixture was allowed towarm to rt and stirred at rt overnight. Saturated aqueous NaHCO₃ (20 mL)was added, CH₂C₂ was removed in vacuo, and the remaining mixture wasextracted with EtOAc (3×20 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo to afford 880 mg (99%) ofthe desired mesylate 5, which was used without further purification.

Step 4. Conversion of mesylate 5 to chloride 6 and alcohol 7

Tetrabutylammonium chloride (2.0 g, 7.2 mmol) was added to a solution of5 (880 mg, 1.5 mmol) in toluene (15 mL). The reaction mixture was heatedat 40° C. for 18 h. The cooled mixture was diluted with brine (30 mL)and extracted with EtOAc (3×50 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on silica gel(hexane→EtOAc, gradient) afforded 230 mg (29%) of chloride 6 and 170 mg(27%) of alcohol 7.

Step 5. Desilylation of 6 to give alcohol 7

Tetrabutylammonium fluoride (0.345 mL of a 1.0 M THF solution, 0.345mmol) was added to a solution of 6 (61 mg, 0.11 mmol) in THF (5.4 mL) atrt. After 18 h at rt, the reaction mixture was partitioned between EtOAc(15 mL) and H₂O (10 mL). The phases were separated and the aqueous phasewas extracted with EtOAc (2×10 mL). The combined organic phase waswashed with brine (50 mL) then dried (MgSO₄), filtered and concentratedin vacuo. Purification of the crude residue by flash columnchromatography on silica gel (hexane→EtOAc, gradient) afforded 10 mg(21%) of alcohol 7.

Step 6. Mitsunobu reaction of 7 and phenol 8 to give 9

Triphenylphosphine (160 mg, 0.61 mmol) and diisopropyl azodicarboxylate(DIAD, 90 μL, 0.49 mmol) were added to a solution of alcohol 7 (170 mg,0.41 mmol) and phenol 8 (see U.S. Provisional Application o. 60/757,696,filed on Jan. 10, 2006, incorporated by reference herein, 81 mg, 0.40mmol) in CH₂Cl₂ (2.0 mL). After stirring 18 h at rt, the mixture waspartitioned between CH₂Cl₂ (15 mL) and saturated aqueous NaHCO₃ (20 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (2×20 mL). The combined organic phase was washed with brine (15mL) then the organic phase was dried (MgSO₄) filtered and concentratedin vacuo. Purification of the residue by flash column chromatography onsilica gel (hexane→EtOAc, gradient) afforded 170 mg (70%) of 9.

Step 7. Deprotection of 9 to give 10

Pyridinium p-toluenesulfonate (PPTs, 7 mg, 0.028 mmol) was added to asolution of 9 (170 mg, 0.28 mmol) in methanol (2.8 mL) at rt. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by flash column chromatographyon silica gel (hexane→EtOAc, gradient) afforded 90 mg (62%) of 10.

Step 8. Oxidation of 10 to give 11 and 12

Dess-Martin periodinane (35 mg, 0.083 mmol) was added to a solution of10 (35 mg, 0.068 mmol) in CH₂Cl₂ (3.0 mL) at 0° C. and the mixture wasallowed to warm to rt. After 2 h at rt, the mixture was partitionedbetween CH₂Cl₂ (5 mL) and H₂O (5 mL). The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (2×5 mL). The combined organicphase was washed with brine (5 mL) then the organic phase was dried(MgSO₄) filtered and concentrated in vacuo. Purification of the residueby flash column chromatography on silica gel (hexane→EtOAc, gradient)afforded 30 mg (˜87%) of a mixture of 11 and 12 (approximately 4:1 infavor of 11).

Step 9. Deprotection of 11/12 to give 13.

Rabbit liver esterase (134 units/mg, 6 mg) was added to a mixture of of11 and 12 from step 8 above (15 mg, ˜0.03 mmol) and pH 7.2 buffer (2.4mL). After 10 min at rt, MeCN (0.16 mL) was added. After stirring at rtfor 24 h, the reaction mixture was concentrated to dryness. Purificationof the resulting crude residue by flash column chromatography on silicagel (10% MeOH/CH₂Cl₂) afforded 5 mg (˜40%) of title compound 13.

Synthetic Example 25-{3-[(1S,2S)-2-(3-Chloro-5-hydroxymethyl-phenoxymethyl)-3-oxo-cyclopentyl]-propyl}-phiophene-2-carboxylicacid (15)

Step 1. Deprotection of 11/12 to give 12/13.

Rabbit liver esterase (134 units/mg, 6 mg) was added to a mixture of of11 and 12 from Example 1, step 8 above (15 mg, ˜0.03 mmol) and pH 7.2buffer (2.4 mL). After 10 min at rt, MeCN (0.16 mL) was added. Afterstirring at rt for 24 h, the reaction mixture was concentrated todryness to afford 10 mg (˜73%) of a mixture of 12 and 13 (approximately3:1 in favor of 12), which was taken on without further purification.

Step 2. Hydrogenation of 12/13 to give 14/15

Palladium on carbon (10 wt. %, 1 mg) was added to a mixture of 12 and 13(10 mg, ˜0.022 mmol) in EtOAc (0.42 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (10×) and thereaction mixture was stirred under a balloon of hydrogen for 6 h. Thereaction mixture was filtered through celite, washing with EtOAc, andthe filtrate was concentrated in vacuo. Purification of the resultingcrude residue by flash column chromatography on silica gel (10%MeOH/CH₂Cl₂) afforded 7 mg (˜68%) of ester 14 and 2.7 mg (30%) of titlecompound 15.

It is envisioned that intermediates such as 12 may react withnucleophiles such as alkyl copper reagents to afford compounds that havealkyl groups at C-9. It is further envisioned that intermediates such as14 may be reacted with lithium diisopropylamide (LDA, or some othersuitable base) followed by an electrophile such as an alkyl halide ordimethyl dioxirane to afford compounds that have an alkyl group or ahydroxyl group at C-10. It is also envisioned that intermediates such as12 may react with appropriate reagents such that an epoxide or diol atC-9-C-10 may result. Furthermore, intermediates such as 12 and 14 mayserve as precursor to compounds in which the ketone has been replaced bya chloro, fluoro, or cyano group. In these cases, the ketone is firstreduced to the corresponding alcohol, which is then converted into thecorresponding mesylate, which then is converted into the desired halo orcyano moiety. The intermediate alcohol and its corresponding ether andester derivatives are also desired.

Biology Examples Binding Data Ki

Competition binding experiments were performed in a medium containingHank's balanced salt solution, Hepes 20 mM, pH 7.3, membranes (˜60 μgprotein) or 2×10⁵ cells from HEK 293 cells stably expressing human EP2receptors, [³H]PGE2 (10 nM) and various concentrations of test compoundsin a total volume of 300 μl. Reaction mixtures were incubated at 23° C.for 60 min, and were filtered over Whatman GF/B filters under vacuum.Filters were washed three times with 5 ml ice-cold buffer containing 50mM Tris/HCl (pH 7.3). Non-specific binding was estimated in the presenceof excess unlabeled PGE2 (10 μM). Binding data fitted to the bindingmodel for a single class of binding sites, using nonlinear regressionanalysis. 10₅₀ values thus obtained were converted to Ki using theequation of Ki=(IC₅₀/(1+[L]/K_(D)) where [L] represents PGE2concentration (10 nM) and K_(D) the dissociation constant for [³H]PGE2at human EP2 receptors (40 nM).

Radioligand Binding Cells Stably Expressing EP1, EP2, EP4 and FPReceptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors were washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H]-17-phenylPGF₂ (5 nM) were performed in a 100 μI volume for 60 min. Bindingreactions were started by adding plasma membrane fraction. The reactionwas terminated by the addition of 4 ml ice-cold TRIS-HCl buffer andrapid filtration through glass fiber GF/B filters using a Brandel cellharvester. The filters were washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-] PGE2 (specific activity 180 Ci mmol) was used as the radioligandfor EP receptors. [³H] 17-phenyl PGF_(2α) was employed for FP receptorbinding studies. Binding studies employing EP₁, EP₂, EP₄ and FPreceptors were performed in duplicate in at least three separateexperiments. A 200 μl assay volume was used. Incubations were for 60 minat 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF_(2α) and non-specific binding determined with10⁻⁵M of unlabeled PGE₂, or 17-phenyl PGF_(2α), according to receptorsubtype studied.

Methods for FLIPR™ Studies (a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEPi; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM I-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/mI streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEPi;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well was then expressed relative to the controls.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3.

cAMP Assay

A 384-well drug plate was prepared to contain 6 test compounds, PGE2 andcAMP in 16 serial dilutions in triplicate, using a Biomek station.HEK-EBNA cells expressing a target PG receptor subtype (EP2 or EP4) weresuspended in a stimulation buffer (HBSS, 0.1% BSA, 0.5 mM IBMX and 5 mMHEPES, pH 7.4) in a density of 10⁴ cells/5 μl. The reaction wasinitiated by mixing 5 μL drug dilutions with 5 μl of HEK-EBNA cells in awell, carried out for 30 min at room temperature, and followed by theaddition of 5 μl anti-cAMP acceptor beads in the control buffer withTween-20 (25 mM NaCl, 0.03% Tween-20, 5 mM HEPES, pH7.4). After 30 minin the dark at room temperature, the mixtures were incubated with 15 μlbiotinylated-cAMP/strepavidin donor beads in Lysis/Detection buffer(0.1% BSA, 0.3% Tween-20 and 5 mM HEPES, pH7.4) for 45 min at the roomtemperature. Fluorescence changes were read using a Fusion-alpha HTmicroplate reader.

The results of the binding and activity studies, presented in Table 1below, demonstrate that the compounds disclosed herein are selectiveprostaglandin EP2 agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, and other diseases or conditions.

TABLE 1 EP2 data EP4 data flipr cAMP flipr Other Receptors (EC50 in nM)Structure EC50 EC50 Ki EC50 KI hFP hEP1 hEP3A hTP hIP hDP

NT 8.7 201 NA NT NA NA NA NA NA NA

NT 457 300 NA >10000 NT NT NT NT NT NT

Treatment Examples

The following are hypothetical examples demonstrating how a person maybe treated with the compounds disclosed herein.

Treatment Example 1

An aqueous liquid containing 0.1% of H1 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 2

An aqueous liquid containing 0.1% of H2 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 3

An aqueous liquid containing 0.1% of H3 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 4

An aqueous liquid containing 0.1% of H4 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 5

An aqueous liquid containing 0.1% of H5 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 6

An aqueous liquid containing 0.1% of H6 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 7

An aqueous liquid containing 0.1% of H7 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 8

An aqueous liquid containing 0.1% of H8 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 9

An aqueous liquid containing 0.1% of H9 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

Treatment Example 10

An aqueous liquid containing 0.1% of H10 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 11

An aqueous liquid containing 0.1% of H11 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 12

An aqueous liquid containing 0.1% of H12 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 13

An aqueous liquid containing 0.1% of H13 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 14

An aqueous liquid containing 0.1% of H14 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 15

An aqueous liquid containing 0.1% of H15 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 16

An aqueous liquid containing 0.1% of H16 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 17

An aqueous liquid containing 0.1% of H17 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 18

An aqueous liquid containing 0.1% of H18 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 19

An aqueous liquid containing 0.1% of H19 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 20

An aqueous liquid containing 0.1% of H₂O is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 21

An aqueous liquid containing 0.1% of H21 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 22

An aqueous liquid containing 0.1% of H22 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 23

An aqueous liquid containing 0.1% of H23 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 24

An aqueous liquid containing 0.1% of H24 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 25

An aqueous liquid containing 0.1% of H25 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 26

An aqueous liquid containing 0.1% of H26 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 27

An aqueous liquid containing 0.1% of H27 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 28

An aqueous liquid containing 0.1% of H28 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 29

An aqueous liquid containing 0.1% of H29 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 30

An aqueous liquid containing 0.1% of H30 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 31

An aqueous liquid containing 0.1% of H31 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 32

An aqueous liquid containing 0.1% of H32 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 33

An aqueous liquid containing 0.1% of H33 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 34

An aqueous liquid containing 0.1% of H34 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 35

An aqueous liquid containing 0.1% of H35 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 36

An aqueous liquid containing 0.1% of H36 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 37

An aqueous liquid containing 0.1% of H37 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 38

An aqueous liquid containing 0.1% of H38 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 39

An aqueous liquid containing 0.1% of H39 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 40

An aqueous liquid containing 0.1% of H40 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 41

An aqueous liquid containing 0.1% of H41 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 42

An aqueous liquid containing 0.1% of H42 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 43

An aqueous liquid containing 0.1% of H43 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 44

An aqueous liquid containing 0.1% of H44 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 45

An aqueous liquid containing 0.1% of H45 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 46

An aqueous liquid containing 0.1% of H46 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 47

An aqueous liquid containing 0.1% of H47 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 48

An aqueous liquid containing 0.1% of H48 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 49

An aqueous liquid containing 0.1% of H49 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 50

An aqueous liquid containing 0.1% of HSO is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 51

An aqueous liquid containing 0.1% of H51 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 52

An aqueous liquid containing 0.1% of H52 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 53

An aqueous liquid containing 0.1% of H53 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 54

An aqueous liquid containing 0.1% of H54 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 55

An aqueous liquid containing 0.1% of H55 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 56

An aqueous liquid containing 0.1% of H56 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 57

An aqueous liquid containing 0.1% of H57 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 58

An aqueous liquid containing 0.1% of H58 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 59

An aqueous liquid containing 0.1% of H59 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 60

An aqueous liquid containing 0.1% of H60 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 61

An aqueous liquid containing 0.1% of H61 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 62

An aqueous liquid containing 0.1% of H62 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 63

An aqueous liquid containing 0.1% of H63 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

Treatment Example 64

An aqueous liquid containing 0.1% of H64 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound having a formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond; Y isan organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O;or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced by S or O; U¹ is independently O; S; F; Cl; Br; I;CN; or O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms ; J¹ and J² areindependently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkyl having 1, 2, 3,4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms;or CF₃; and B is aryl or heteroaryl.
 2. A compound which is a carboxylicacid or a bioisostere thereof, said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond; A is—(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; U¹ isindependently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3, 4, 5 or6 carbon atoms; J¹ and J² are independently hydrogen; F; Cl, Br; I; O;OH; CN; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1,2, 3, 4, 5, or 6 carbon atoms; or CF₃; and B is aryl or heteroaryl. 3.The compound according to claim 1 wherein Y is selected from CO₂R²,CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.
 4. The compound of claim 3, wherein saidcompound has a formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 5.The compound of claim 3, wherein said compound has a formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 6.The compound of claim 3 wherein A is —(CH₂)₃Ar—, —O(CH₂)₂Ar—,—CH₂OCH₂Ar—, —(CH₂)₂OAr, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—, or —(CH₂)₂OAr,wherein Ar is monocyclic interheteroarylene.
 7. The compound of claim 6wherein Ar is interthienylene.
 8. The compound of claim 6 wherein Ar isinterthiazolylene.
 9. The compound of claim 6 wherein Ar isinteroxazolylene.
 10. The compound of claim 7 wherein A is5-(3-propyl)thiophen-2-yl.
 11. The compound of claim 3 wherein A is6-hexyl.
 12. The compound of claim 3 wherein A is (Z)-6-hex-4-enyl. 13.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 14.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 15.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 16.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 17.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 18.The compound of claim 3 having the formulala

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 19.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 20.The compound of claim 3 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof. 21.The compound of claim 6 wherein B is substituted or unsubstitutedphenyl.
 22. The compound of claim 21 wherein B has 1, 2, 3, 4, or 5substituents, wherein each substituent has one or more carbon, fluorine,chlorine, bromine, or oxygen atoms; and wherein all substituents takentogether consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0,1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms,0, 1, 2 or 3 bromine atoms, and 0, 1, 2 or 3 oxygen atoms.
 23. Thecompound of claim 22 selected from5-{3-[(1S,5S)-5-(3-Chloro-5-hydroxymethyl-phenoxymethyl)-4-oxo-cyclopent-2-enyl]-propyl}-phiophene-2-carboxylicacid; and5-{3-[(1S,2S)-2-(3-Chloro-5-hydroxymethyl-phenoxymethyl)-3-oxo-cyclopentyl]-propyl}-phiophene-2-carboxylicacid.
 24. A method of reducing intraocular pressure or treating glaucomacomprising administering a compound according to claim 1 to a mammal inneed thereof.
 25. The compound of claim 3, wherein said compound has aformula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.